Long telomeres may mean higher cancer risk, UCSF team says

It was a cliche, maybe, but seemed to be true: Bigger is better when it comes to telomeres. For a long time, that was what the evidence suggested, anyway.

Telomeres are the protective sheaths at the end of chromosomes that help delay cellular aging and fend off disease. Multiple studies have shown that people with long telomeres tend to be healthier and live longer, by five years or so, than those with short telomeres.

Long telomeres have been associated with lower incidences of diabetes and heart disease and lower levels of stress. People with long telomeres tend to eat better and exercise more than those with short telomeres.

But increasingly scientists have begun to wonder if there might be a downside - if bigger isn't always necessarily better.

Scientists have hypothesized that long telomeres may contribute to cancer development, and earlier studies have found links between telomere maintenance and breast, prostate and colon cancer.

Now, a team of UCSF researchers has produced some of the strongest evidence that having long telomeres, while certainly protective in many ways, may leave people vulnerable to certain types of cancer.

In a paper released this week, the UCSF scientists reported that people who are genetically predisposed to having long telomeres also have an increased risk - by about 30 to 40 percent - of developing gliomas, a deadly brain tumor. The actual risk of cancer is still very small - less than 1 percent of people with the genetic predisposition will develop gliomas - but the findings show that telomere length is not as black and white as the earliest studies might have suggested.

"People have thought there might be paradoxical effects of telomeres, but this study is a really vivid demonstration of that," said Margaret Wrensch, an author of the new report who runs a glioma study at UCSF.

With telomeres, as with most areas of human biology and behavior, that gray area known as "moderation" may be the key to overall health, added Kyle Walsh, also an author, who is a cancer genetics scientist at UCSF.

"We've operated under the assumption that long telomeres are good and short telomeres are bad," Walsh said. "But telomeres are a little more complex than perhaps we've been thinking about them."

Telomeres are short chains of chemical coding that cap off the ends of chromosomes, the double-stranded strings of DNA that contain our genetic material in the nucleus of every cell. UCSF molecular biologist Elizabeth Blackburn, along with two other scientists, won the Nobel Prize in 2009 for discovering telomeres in the 1970s and later identifying the enzyme called telomerase that builds and maintains the protective caps.

Scientists often compare telomeres to the plastic tips at the end of shoelaces - they protect the laces and keep them from unraveling. But that's just one piece of their job.

Stabilizing DNA

Telomeres also help stabilize DNA during replication. Without telomeres, the strings of DNA would shorten each time a cell divided and reproduced. As long as there's a healthy strip of telomere at the end of a chromosome, a cell can keep dividing, providing new material to grow blood, bone, muscle and other tissues that must be replenished over a lifetime.

Eventually, telomeres do shorten, but the longer a telomere is, the longer a cell can safely reproduce. Scientists believe that short telomeres not only shorten the reproductive lives of cells but also weaken them, leaving them prone to damage that can eventually lead to disease.

And so, naturally, scientists also believed that long telomeres were a marker of good health.

"Telomeres are something that we've known were associated with youth and with healthful aging," Walsh said. "All these healthful things were associated with them."

The UCSF study looked at genomic data from 1,644 patients with glioma, many of them participants in Wrensch's glioma study, and 7,736 healthy people. Earlier work by Wrensch and other colleagues had found that people with genetic variations in a gene called TERT had a higher risk of developing glioma. The new study found that variants in the gene called TERC also increased the risk.

What piqued the scientists' interest was that both TERT and TERC are necessary for the release of telomerase, which controls production of telomeres. But they couldn't tell from their study results what the gene variants did - whether they increased the release of telomerase, reduced it, or had some other effect.

So Walsh reached out to scientists at the University of Leicester in Britain, where they had collected data on gene variants and telomere length for 40,000 people. The Leicester data showed that the same TERT and TERC variants that increased the risk of glioma also predisposed people to have long telomeres.

The results showed a very strong connection between glioma risk and telomere length, Wrensch said.

"It's rare in epidemiology to get such clarity," she said. "There had been theories about possibly increasing carcinogenesis with telomere length. We haven't had the tools and techniques until recently to really nail down these hypotheses."

What that relationship may mean is still unclear, though. Walsh suggested that it's possible that long telomeres that allow cells more time to divide may also leave them more open to acquiring mutations, which can lead to cancer. Long telomeres may also mean that the cancer cells are able to spread longer and faster - tumors are, after all, built on cells that divide and spread out of control.

Another possibility is that telomerase production is the link between long telomeres and cancer risk. Perhaps the gene variants cause increased production of telomerase, which in turn leads to long telomeres while also giving a boost to cancer cells, said Dr. Steven Artandi, a Stanford oncologist who studies telomerase and cancer.

In other words, long telomeres aren't necessarily causing cancer.

"Long telomeres might just be a biomarker or indication of what the gene variant is actually doing," Artandi said.

The UCSF study, he said, adds to the increasing complexity of telomeres and the role they play in health and aging. Short telomeres are undoubtedly bad - aside from being associated with an increased risk of diseases like diabetes, they are very closely connected to conditions like pulmonary fibrosis, anemia and even certain types of cancer, Artandi said.

Improving treatments

And long telomeres - even if they may leave people vulnerable to cancers - are undoubtedly also associated with other signs of good health, Walsh said.

"I've talked to neuro-oncologists who have said that these glioma patients are much healthier than the general population," he said. "Very frequently these are very virile, robust, healthy people, who have taken good care of themselves and haven't been sick a day in their life. And then they're diagnosed with this malignant brain tumor."

Research that better defines the associations between long and short telomeres, telomerase production and overall health may lead to improved treatments for diseases like glioma or even therapies to prevent illness, Artandi said.

"I think it depends on where you are on the telomere curve," he said.

Somewhere in the middle is probably about right, but no one knows where the middle is, just yet, scientists said.

"It's the extremes of the distribution that cause problems. Most of us are in the middle," Walsh said. "But it does make you question this idea that, 'Oh, if we just lengthened telomeres, that would be great.' Everything turns out to be more complicated."